The purpose of this K01 application is to foster the candidate's career development in clinical and translational research on aging. His long term career goal is to become an independent translational investigator in functional decline and rehabilitation of older adults. After postdoctoral training in basic human skeletal muscle research, the applicant became interested in translational research on aging through his interactions with the UTMB Claude D. Pepper Older Americans Independence Center (OAIC). He now seeks additional training to gather a better understanding of the issues underlying functional decline and rehabilitation in older adults. The career development plan includes both formal and informal training combined with apprentice-style learning activities. A diverse mentoring team comprised of Drs. Volpi, Ottenbacher and Paddon-Jones will guide this development. UTMB is exceptionally well suited to foster the candidate's career development, as it provides a very collaborative environment for multidisciplinary research. Specifically, the candidate will continue to receive educational and core resource support from the UTMB OAIC and CTSA. The goal of the research project is to determine how aging and inactivity reduce the muscle anabolic effect of nutrients and lead to muscle and functional loss. The central hypothesis is that aging reduces mTORC1 signaling and the expression of skeletal muscle amino acid transporters in response to anabolic stimulation leading to reduced muscle adaptation to increased intracellular amino acid requirements. We further hypothesize that inactivity exacerbates this effect with significant muscle and functional loss, and rehabilitation restores muscle signaling, metabolism and function to baseline values. Controlled bed rest is a very powerful model of accelerated muscle loss and dysfunction via a reduction in muscle protein synthesis. The degree of muscle and functional loss achieved with bed rest significantly increases with aging. We will test in healthy subjects the following specific aims: 1) To determine if aging blunts the physiological upregulation of mTORC1 signaling and skeletal muscle amino acid transporters to amino acid ingestion and decreases intracellular amino acid availability and muscle protein anabolism. 2) To determine if physical inactivity (bed rest) further exacerbates the age-induced reduction in mTORC1 signaling and amino acid transporter expression in response to amino acid ingestion and induces a larger muscle and functional loss in older as compared to younger subjects. 3) To determine if physical rehabilitation can restore muscle signaling, metabolism and function to levels not different from the pre-bed rest condition. The pilot data collected will be used for future R01 submissions to identify mechanisms and novel targets for interventions to improve muscle function and preserve physical independence in older adults. PUBLIC HEALTH RELEVANCE: We want to understand the mechanisms that cause older adults to lose physical function, and find novel treatments for promotion of independence. We are interested in discovering how a reduced response to nutrients due to aging and physical inactivity (i.e., hospitalization) produces muscle loss in seniors, and if physical rehabilitation can restore strength and function. This study is especially important given the current rapid increase in the number and proportion of older individuals in our society.